A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC
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Gianluca Occhi1,*, Susi Barollo2,*, Daniela Regazzo2, Loris Bertazza2, Francesca Galuppini3, Vincenza Guzzardo3, Marie Lise Jaffrain-Rea4,5, Federica Vianello6, Denis Ciato2, Filippo Ceccato2, Sara Watutantrige-Fernando2, Andrea Bisognin1, Stefania Bortoluzzi7, Gianmaria Pennelli3, Marco Boscaro2, Carla Scaroni2, Caterina Mian2
1Department of Biology, University of Padova, Padova, Italy
2Endocrinology Division, Department of Medicine, Hospital/University of Padova, Padova, Italy
3Surgical Pathology & Cytopathology Unit, Department of Medicine, Hospital/University of Padova, Padova, Italy
4Department of Clinical and Biotechnological Sciences, University of L’Aquila, L’Aquila, Italy
5Neuromed Institute, Department of Neurological Sciences, University of L’Aquila, L’Aquila, Italy
6Department of Radiotherapy, Istituto Oncologico del Veneto, IOV-IRCCS, Padova, Italy
7Department of Molecular Medicine, University of Padova, Padova, Italy
*These authors have contributed equally to this work
Gianluca Occhi, e-mail: email@example.com
Keywords: papillary thyroid cancer, aryl hydrocarbon receptor, BRAF, gene expression, meta-analysis
Received: April 30, 2015 Accepted: September 03, 2015 Published: September 16, 2015
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice.
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